AU645874B2 - Treatment for osteoporosis using growth hormone release factor (GRF) in combination with parathyroid hormone (PTH) - Google Patents
Treatment for osteoporosis using growth hormone release factor (GRF) in combination with parathyroid hormone (PTH)Info
- Publication number
- AU645874B2 AU645874B2 AU90735/91A AU9073591A AU645874B2 AU 645874 B2 AU645874 B2 AU 645874B2 AU 90735/91 A AU90735/91 A AU 90735/91A AU 9073591 A AU9073591 A AU 9073591A AU 645874 B2 AU645874 B2 AU 645874B2
- Authority
- AU
- Australia
- Prior art keywords
- grf
- pth
- osteoporosis
- administered
- treatment
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- 108090000445 Parathyroid hormone Proteins 0.000 title claims abstract description 32
- 239000000199 parathyroid hormone Substances 0.000 title claims abstract description 25
- 208000001132 Osteoporosis Diseases 0.000 title claims abstract description 16
- 238000011282 treatment Methods 0.000 title claims description 26
- 102000003982 Parathyroid hormone Human genes 0.000 title claims description 25
- 229960001319 parathyroid hormone Drugs 0.000 title abstract description 24
- 102000018997 Growth Hormone Human genes 0.000 title description 9
- 108010051696 Growth Hormone Proteins 0.000 title description 9
- 239000000122 growth hormone Substances 0.000 title description 9
- 210000000988 bone and bone Anatomy 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 33
- 101710142969 Somatoliberin Proteins 0.000 claims abstract description 27
- 208000001685 postmenopausal osteoporosis Diseases 0.000 claims abstract description 9
- 101001135770 Homo sapiens Parathyroid hormone Proteins 0.000 claims description 10
- 101001135995 Homo sapiens Probable peptidyl-tRNA hydrolase Proteins 0.000 claims description 10
- 102000058004 human PTH Human genes 0.000 claims description 10
- 230000001965 increasing effect Effects 0.000 claims description 5
- 101000825742 Homo sapiens Somatoliberin Proteins 0.000 claims description 3
- OGBMKVWORPGQRR-UMXFMPSGSA-N teriparatide Chemical compound C([C@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)[C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CNC=N1 OGBMKVWORPGQRR-UMXFMPSGSA-N 0.000 claims 1
- 239000000095 Growth Hormone-Releasing Hormone Substances 0.000 abstract description 13
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 abstract description 5
- 239000011575 calcium Substances 0.000 abstract description 5
- 229910052791 calcium Inorganic materials 0.000 abstract description 5
- 238000009825 accumulation Methods 0.000 abstract description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 abstract description 4
- 239000011707 mineral Substances 0.000 abstract description 4
- 230000000737 periodic effect Effects 0.000 abstract description 2
- 102100036893 Parathyroid hormone Human genes 0.000 abstract 2
- 102100022831 Somatoliberin Human genes 0.000 abstract 2
- 102000038461 Growth Hormone-Releasing Hormone Human genes 0.000 description 12
- 230000000694 effects Effects 0.000 description 10
- 206010017076 Fracture Diseases 0.000 description 7
- 206010065687 Bone loss Diseases 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 230000001817 pituitary effect Effects 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 4
- 229940088597 hormone Drugs 0.000 description 4
- 239000005556 hormone Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 206010062767 Hypophysitis Diseases 0.000 description 3
- 125000003275 alpha amino acid group Chemical group 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 210000003635 pituitary gland Anatomy 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 208000010392 Bone Fractures Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 241000282414 Homo sapiens Species 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 210000004349 growth plate Anatomy 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000009245 menopause Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 206010000599 Acromegaly Diseases 0.000 description 1
- 206010056438 Growth hormone deficiency Diseases 0.000 description 1
- 208000029725 Metabolic bone disease Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010049088 Osteopenia Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000035850 clinical syndrome Diseases 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 230000000849 parathyroid Effects 0.000 description 1
- 210000002990 parathyroid gland Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 239000003488 releasing hormone Substances 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 210000002303 tibia Anatomy 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
- A61P5/12—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH for decreasing, blocking or antagonising the activity of the posterior pituitary hormones
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Endocrinology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Diabetes (AREA)
- Rheumatology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US61754390A | 1990-11-26 | 1990-11-26 | |
US617543 | 2000-07-14 |
Publications (2)
Publication Number | Publication Date |
---|---|
AU9073591A AU9073591A (en) | 1992-06-25 |
AU645874B2 true AU645874B2 (en) | 1994-01-27 |
Family
ID=24474060
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU90735/91A Ceased AU645874B2 (en) | 1990-11-26 | 1991-11-01 | Treatment for osteoporosis using growth hormone release factor (GRF) in combination with parathyroid hormone (PTH) |
Country Status (13)
Country | Link |
---|---|
US (1) | US5164368A (de) |
EP (1) | EP0559751B1 (de) |
JP (1) | JP2557779B2 (de) |
AT (1) | ATE150648T1 (de) |
AU (1) | AU645874B2 (de) |
CA (1) | CA2096350C (de) |
DE (1) | DE69125394T2 (de) |
DK (1) | DK0559751T3 (de) |
ES (1) | ES2099245T3 (de) |
FI (1) | FI106776B (de) |
IE (1) | IE913858A1 (de) |
NZ (1) | NZ240482A (de) |
WO (1) | WO1992009304A1 (de) |
Families Citing this family (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5494919A (en) * | 1993-11-09 | 1996-02-27 | Merck & Co., Inc. | 2-substituted piperidines, pyrrolidines and hexahydro-1H-azepines promote release of growth hormone |
US5492916A (en) * | 1993-12-23 | 1996-02-20 | Merck & Co., Inc. | Di- and tri-substituted piperidines, pyrrolidines and hexahydro-1H-azepines promote release of growth hormone |
US5492920A (en) * | 1993-12-10 | 1996-02-20 | Merck & Co., Inc. | Piperidine, pyrrolidine and hexahydro-1H-azepines promote release of growth hormone |
CZ134296A3 (en) * | 1993-11-09 | 1996-12-11 | Merck & Co Inc | Piperidine, pyrrolidine and hexahydro-1h-azepine derivatives, process of their preparation and pharmaceutical compositions containing thereof |
US5721251A (en) * | 1993-12-10 | 1998-02-24 | Merck & Co., Inc. | Piperidine, pyrrolidine and hexahydro-1H-azepines promote release of growth hormone |
US5721250A (en) * | 1993-12-23 | 1998-02-24 | Merck & Co. Inc. | Di-and tri-substituted piperidines, pyrrolidines and hexahydro-1H-azepines promote release of growth hormone |
US5942496A (en) * | 1994-02-18 | 1999-08-24 | The Regent Of The University Of Michigan | Methods and compositions for multiple gene transfer into bone cells |
US5962427A (en) * | 1994-02-18 | 1999-10-05 | The Regent Of The University Of Michigan | In vivo gene transfer methods for wound healing |
US5763416A (en) * | 1994-02-18 | 1998-06-09 | The Regent Of The University Of Michigan | Gene transfer into bone cells and tissues |
US6074840A (en) * | 1994-02-18 | 2000-06-13 | The Regents Of The University Of Michigan | Recombinant production of latent TGF-beta binding protein-3 (LTBP-3) |
US6551618B2 (en) | 1994-03-15 | 2003-04-22 | University Of Birmingham | Compositions and methods for delivery of agents for neuronal regeneration and survival |
US5731317A (en) * | 1995-03-10 | 1998-03-24 | Merck & Co., Inc. | Bridged piperidines promote release of growth hormone |
US5700775A (en) * | 1995-03-24 | 1997-12-23 | Gutniak; Mark K. | Method and treatment composition for decreasing patient time in catabolic state after traumatic injury |
US5559128A (en) * | 1995-04-18 | 1996-09-24 | Merck & Co., Inc. | 3-substituted piperidines promote release of growth hormone |
US5869041A (en) * | 1996-01-12 | 1999-02-09 | The Miriam Hospital | Delivery of bioactive compounds to an organism |
HN1996000101A (es) * | 1996-02-28 | 1997-06-26 | Inc Pfizer | Terapia combinada para la osteoporosis |
AU3025997A (en) * | 1996-05-31 | 1998-01-05 | Novo Nordisk A/S | Growth hormone component and bone anti-resorptive agent in cyclic (coherence) treatment of osteoporosis |
SE9702401D0 (sv) * | 1997-06-19 | 1997-06-19 | Astra Ab | Pharmaceutical use |
AU2002300896B2 (en) * | 1997-06-19 | 2006-03-30 | Nps Pharmaceuticals, Inc. | Method of enhancing bone mineral density |
DE69840361D1 (de) | 1997-07-30 | 2009-01-29 | Univ Emory | Neue knochenmineralisierungsproteine, dna, vektoren, expressionssysteme |
US7923250B2 (en) | 1997-07-30 | 2011-04-12 | Warsaw Orthopedic, Inc. | Methods of expressing LIM mineralization protein in non-osseous cells |
EP1119251A4 (de) * | 1998-10-07 | 2004-03-24 | Univ Arkansas | Verfahren für das screening auf wirkstoffe für die anabole knochentherapie, die die apoptosis kontrollieren, und ihre verwendung |
WO2000028982A2 (en) | 1998-11-19 | 2000-05-25 | The Board Of Trustees For The University Of Arkansas | Increasing bone strength with selected bisphosphonates |
US20060052306A1 (en) * | 2004-05-10 | 2006-03-09 | Nastech Pharmaceutical Company Inc. | GRAS composition for enhanced mucosal delivery of parathyroid hormone |
CN101151048A (zh) | 2004-05-10 | 2008-03-26 | 纳斯泰克制药公司 | 增强甲状旁腺激素粘膜递送的组合物和方法 |
US20070173447A1 (en) * | 2005-10-25 | 2007-07-26 | Nastech Pharmaceutical Company Inc. | Method for treating osteoporosis by intranasal delivery of teriparatide with an anti-resorptive agent |
CA2628945A1 (en) * | 2005-11-10 | 2007-05-24 | Board Of Control Of Michigan Technological University | Black bear parathyroid hormone and methods of using black bear parathyroid hormone |
US20080051332A1 (en) * | 2005-11-18 | 2008-02-28 | Nastech Pharmaceutical Company Inc. | Method of modulating hematopoietic stem cells and treating hematologic diseases using intranasal parathyroid hormone |
CN104370909B (zh) | 2009-12-01 | 2018-09-11 | Abbvie 公司 | 三环化合物 |
AU2009356227A1 (en) | 2009-12-07 | 2012-06-21 | Michigan Technological University | Black bear parathyroid hormone and methods of using black bear parathyroid hormone |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4833123A (en) * | 1987-10-08 | 1989-05-23 | Sumitomo Chemical Company Limited | Yellow dye-donor element used in thermal transfer and thermal transfer and thermal transfer sheet using it |
AU3033189A (en) * | 1988-01-29 | 1989-08-25 | Upjohn Company, The | Growth hormone releasing factor analogs |
US4870094A (en) * | 1984-05-02 | 1989-09-26 | Uniroyal Chemical Company, Inc. | Substituted imidazoles and triazoles |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4710382A (en) * | 1985-09-27 | 1987-12-01 | Recker Robert R | Treatment for osteoporosis using hGRF(1-40)NH2 |
US4870054A (en) * | 1985-09-27 | 1989-09-26 | Recker Robert R | Treatment for osteoporosis using GRF or a biologically active analog thereof |
US4833125A (en) * | 1986-12-05 | 1989-05-23 | The General Hospital Corporation | Method of increasing bone mass |
-
1991
- 1991-11-01 EP EP92900612A patent/EP0559751B1/de not_active Expired - Lifetime
- 1991-11-01 JP JP4501851A patent/JP2557779B2/ja not_active Expired - Fee Related
- 1991-11-01 AT AT92900612T patent/ATE150648T1/de not_active IP Right Cessation
- 1991-11-01 WO PCT/US1991/008106 patent/WO1992009304A1/en active IP Right Grant
- 1991-11-01 AU AU90735/91A patent/AU645874B2/en not_active Ceased
- 1991-11-01 DK DK92900612.0T patent/DK0559751T3/da active
- 1991-11-01 DE DE69125394T patent/DE69125394T2/de not_active Expired - Fee Related
- 1991-11-01 ES ES92900612T patent/ES2099245T3/es not_active Expired - Lifetime
- 1991-11-01 CA CA002096350A patent/CA2096350C/en not_active Expired - Fee Related
- 1991-11-04 US US07/787,051 patent/US5164368A/en not_active Expired - Lifetime
- 1991-11-05 NZ NZ240482A patent/NZ240482A/en unknown
- 1991-11-05 IE IE385891A patent/IE913858A1/en not_active IP Right Cessation
-
1993
- 1993-05-26 FI FI932385A patent/FI106776B/fi active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4870094A (en) * | 1984-05-02 | 1989-09-26 | Uniroyal Chemical Company, Inc. | Substituted imidazoles and triazoles |
US4833123A (en) * | 1987-10-08 | 1989-05-23 | Sumitomo Chemical Company Limited | Yellow dye-donor element used in thermal transfer and thermal transfer and thermal transfer sheet using it |
AU3033189A (en) * | 1988-01-29 | 1989-08-25 | Upjohn Company, The | Growth hormone releasing factor analogs |
Also Published As
Publication number | Publication date |
---|---|
JP2557779B2 (ja) | 1996-11-27 |
FI932385A (fi) | 1993-05-26 |
EP0559751A1 (de) | 1993-09-15 |
EP0559751A4 (en) | 1994-07-13 |
ATE150648T1 (de) | 1997-04-15 |
DE69125394T2 (de) | 1997-08-21 |
JPH06502863A (ja) | 1994-03-31 |
FI932385A0 (fi) | 1993-05-26 |
WO1992009304A1 (en) | 1992-06-11 |
DE69125394D1 (de) | 1997-04-30 |
EP0559751B1 (de) | 1997-03-26 |
FI106776B (fi) | 2001-04-12 |
US5164368A (en) | 1992-11-17 |
CA2096350C (en) | 2001-10-16 |
AU9073591A (en) | 1992-06-25 |
CA2096350A1 (en) | 1992-05-27 |
DK0559751T3 (da) | 1997-10-06 |
NZ240482A (en) | 1997-06-24 |
ES2099245T3 (es) | 1997-05-16 |
IE913858A1 (en) | 1992-06-03 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |